• RHBDF1 deficiency reduces PERK, pPERK, and peIF2α levels in breast cancer cells, which can be restored by RHBDF1 overexpression but not by IRE1 or ATF6.
• RHBDF1 activates the JNK pathway, leading to nuclear translocation of FoxO3, which is essential for PERK expression.
• The study establishes a novel RHBDF1-JNK-FoxO3-PERK axis in the unfolded protein response, highlighting RHBDF1's role in ER protein homeostasis.
• These findings suggest that targeting RHBDF1 or its downstream pathway could be a potential therapeutic strategy for breast cancer.